Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, To-on 791-0295, Japan.
Int J Mol Sci. 2023 Jan 28;24(3):2509. doi: 10.3390/ijms24032509.
Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease all over the world. Therapeutic strategies targeting its multidirectional pathways are required. Particularly, fibrosis is closely associated with its prognosis. We previously found that B cell-activating factor (BAFF) is associated with severity of NAFLD. Here, we determined the direct in vivo role of BAFF in the development of liver fibrosis. Histological and biochemical analyses were performed using wild-type and BAFF-deficient mice. We established a murine model of non-alcoholic steatohepatitis (NASH) using carbon tetrachloride injection accompanied by high-fat/high-cholesterol diet feeding. Additionally, in vitro analysis using mouse macrophage-like cell line RAW264.7 and primary hepatic stellate cells was performed. Hepatic steatosis and inflammation, and most importantly, the progression of liver fibrosis, were ameliorated in BAFF-deficient mice compared to those wild-type mice in our model. Additionally, BAFF deficiency reduced the number of CD11c M1-type macrophages in the liver. Moreover, BAFF stimulated RAW264.7 cells to secrete nitric oxide and tumor necrosis factor α, which drove the activation of hepatic stellate cells. This indicates that BAFF plays a crucial role in NASH development and may be a promising therapeutic target for NASH.
非酒精性脂肪性肝病（NAFLD）是全世界最常见的慢性肝脏疾病。需要针对其多向途径的治疗策略。特别是纤维化与疾病的预后密切相关。我们之前发现 B 细胞激活因子（BAFF）与 NAFLD 的严重程度有关。在这里，我们确定了 BAFF 在肝纤维化发展中的直接体内作用。使用野生型和 BAFF 缺陷型小鼠进行组织学和生化分析。我们使用四氯化碳注射联合高脂肪/高胆固醇饮食喂养建立了非酒精性脂肪性肝炎（NASH）的小鼠模型。此外，还使用小鼠巨噬细胞样细胞系 RAW264.7 和原代肝星状细胞进行了体外分析。与野生型小鼠相比，在我们的模型中，BAFF 缺陷型小鼠的肝脂肪变性和炎症，以及最重要的肝纤维化进展得到改善。此外，BAFF 缺陷减少了肝脏中 CD11c M1 型巨噬细胞的数量。此外，BAFF 刺激 RAW264.7 细胞分泌一氧化氮和肿瘤坏死因子 α，从而驱动肝星状细胞的激活。这表明 BAFF 在 NASH 的发展中起关键作用，可能是 NASH 的有前途的治疗靶点。
